Eukaryotic gene expression is regulated by a complex assortment of different proteins associating with each other. This coming together of different proteins is structurally a subtle and largely unknown field. An understanding of the energetics of protein-protein interactions promises to be an important area for the design of novel proteins that disrupt gene regulation with possible future therapeutic consequences. We have been examining the structural and thermodynamic determinants of leucine zipper dimerization, a coiled coil motif essential for the function of two classes of oncogenic DNA binding proteins, the bZIP and bHLH-Zip motif's. We have been generating structural rules that govern the specificity of leucine zipper dimerization using circular dichroism thermal melts. The main thrust of this work is to use these protein design rules to generate dominant negatives to bZIP proteins. We have been successful in designing a dominant negative to the bZIP protein C/EBP as assayed in a transient transfection assay in a zipper dependent manner. Overexpression of this dominant negative in transgenic mice generates a dominant lethal phenotype with characteristics that are similar to the C/EBP knockout mouse. We are presently putting this dominant negative under tissue specific control to examine the function of the C/EBP family in a more restricted part of the mouse body.